Prostate specific membrane antigen (psma) ligands and uses thereof

Abstract

The present disclosure relates to prostate specific membrane antigen (PSMA) ligands. In particular, the disclosure relates to PSMA ligands having a glutamate-urea-lysine (GUL) moiety, a radioisotope and a chelating agent that can comprise a radiometal.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         Z is tetrazole or COOQ, preferably Z is COOQ; 
         Q is independently H or a protecting group, preferably Q is H; 
         m is an integer selected from the group consisting of 1, 2, 3, 4, and 5, preferably m is 4; 
         q is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6, preferably q is 1; 
         R is selected from the group consisting of C 6 -C 10  aryl and heteroaryl containing 5 to 10 ring atoms, said aryl and heteroaryl being substituted 1 or more times with X; 
         X is −Z—Y; 
         Z is a bond or a C 1 -C 6  alkylene, preferably Z is a bond; 
         Y is a radioisotope; 
         L is a linker selected from the group consisting of C 1 -C 6  alkylene, C 3 -C 6  cycloalkylene and C 6 -C 10  arylene, said alkylene, cycloalkylene and arylene being optionally substituted with one or more substituents selected from: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO2R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR′, —NR′—C(NR″R′″)═NR″″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and —NO 2  in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such groups. R′, R″, R′″ and R″″ each may independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; 
         W is selected from the group consisting of —NR 2 —(C═O), —NR 2 —(C═S), —(C═O)—NR 2 —, and —(C═S)—NR 2 —, preferably, W is —(C═O)—NR 2 —; 
         each occurrence of L and W can be the same or different; 
         R 2 is H or C 1 -C 4  alkyl, preferably R 2 is H; 
         n is an integer selected from the group consisting of 1, 2 and 3; 
         Ch is a chelating agent optionally comprising a metal or a radiometal; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The compound of formula (I) according to  claim 1 , wherein the compound is a compound of formula (Ia), (Ib), (Ic) or (Id): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of formula (I) according to  claim 1 or 2 , wherein Y is a radioisotope selected from the group consisting of  18 F,  34 Cl,  75 Br,  76 Br,  77 Br,  123 I,  124 I,  125 I,  131 I and  211  At, preferably Y is  18 F or  211  At. 
     
     
         4 . The compound of formula (I) according to  claims 1 to 3 , wherein R is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein p is an integer selected from the group consisting of 1, 2, 3, 4, and 5, preferably p is 1; 
         preferably, R is selected from 
       
       
         
           
           
               
               
           
         
       
       and, more preferably R is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of formula (I) according to any one of  claims 1 to 4 , wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of formula (I) according to any one of  claims 1 to 5 , wherein Ch is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and optionally comprises a metal or a radiometal. 
       
     
     
         7 . The compound of formula (I) according to any one of  claims 1 to 6 , wherein L is a linker selected from the group consisting of C 3 -C 6  alkylene optionally substituted with one or more substituents selected from: —OR′, ═O, ═NR′, —NR′R″, -halogen, —OC(O)R′, —C(O)R′, —CO2R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR′, in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such groups. R′, R″, R′″ and R″″ each may independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. 
     
     
         8 . The compound of formula (I) according to any one of  claims 1 to 7 , wherein Ch comprises a metal selected from Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc. 
     
     
         9 . The compound of formula (I) according to  claim 8 , wherein the metal is a radiometal selected from  68 Ga,  64 Cu,  86 Y,  90 Y,  89 Zr,  111 In,  99 mTc,  177 Lu,  153 Sm,  186 Re,  188 Re,  67 Cu,  212 Pb,  225 Ac,  213 Bi,  212 Bi,  212 Pb,  67 Ga,  203 Pb,  47 Sc, and  166 Ho. 
     
     
         10 . The compound of formula (I) according to any one of  claims 1 to 9 , wherein the compound is a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein L .is a linker selected from the group consisting of C 3 -C 6  alkylene optionally substituted with one or more substituents selected from: —OR′, ═O, ═NR′, —NR′R″, -halogen, —OC(O)R′, —C(O)R′, —CO2R′, —C(O)NR′R″, —OC(O) NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR′, in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such groups. R′, R″, R′″ and R″″ each may independently refer to hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. 
       
     
     
         11 . The compound of formula (II) according to  claim 10 , wherein the compound of formula (II) comprises  68 Ga or  67 Ga. 
     
     
         12 . The compound of formula (II) according to  claim 10 , wherein the compound of formula (II) comprises  177 Lu or  176 Lu. 
     
     
         13 . A pharmaceutical composition comprising a compound according to any one of  claims 1 to 12  and at least one pharmaceutically acceptable carrier. 
     
     
         14 . The pharmaceutical composition according to  claim 13 , wherein said composition further comprises a compound comprising i) a PSMA binding ligand, ii) optionally a linker, and iii) a chelating agent optionally comprising a metal or a radiometal. 
     
     
         15 . A compound according to any one of  claims 1 to 12  for use as a drug. 
     
     
         16 . The compound for use according to  claim 15 , wherein said compound is for use in treating cancer, in particular by targeted alpha therapy and by beta radiation. 
     
     
         17 . The compound for use according to  claim 15 or 16 , wherein said compound is for use in treating prostate cancer. 
     
     
         18 . A compound according to any one of  claims 1 to 12  for use in imaging, preferably PET and SPECT. 
     
     
         19 . A compound according to any one of  claims 1 to 12  for use in diagnostic, typically for use in diagnosing cancer disorders, such as PSMA-expressing cancers. 
     
     
         20 . A method for treating cancer, the method comprising contacting cancer cells with a therapeutically efficient amount of a compound according to any one of  claims 1 to 12 . 
     
     
         21 . A method for imaging, the method comprising administering an effective amount of a compound according to any one of  claims 1 to 12  to a subject and detecting the signal derived from the decay of the radioisotope and/or radiometal present in said compound. 
     
     
         22 . A method for diagnosing and/or detecting cancer cells or PSMA-expressing tumors or cells in a subject, the method comprising administering to said subject, preferably a human, a therapeutically efficient amount of a compound according to any one of  claims 1 to 12 , and detecting the signal derived from the decay of the radioisotope and/or radiometal present in said compound.